Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000037665 | SCV000061327 | pathogenic | Noonan syndrome | 2012-02-27 | criteria provided, single submitter | clinical testing | The Phe285Leu variant has been reported in the literature in one sporadic incide nce of Noonan syndrome (Hung 2007). This variant has also been identified in on e individual with clinical features of Noonan syndrome by our laboratory. Addit ionally, a different nucleotide substitution (c.853T>C) resulting in the same am ino acid change has also been identified in several individuals with the clinica l features of Noonan syndrome as well as Noonan-like/multiple giant-cell lesion syndrome both in the literature and by our laboratory (Tartaglia 2002, Nystrom 2 008, Jafarov 2005, Lee 2005, LMM unpublished data). The c.853T>C variant has als o been observed to have occurred de novo in sporadic cases of Noonan syndrome. In summary, the Phe285Leu variant meets our criteria to be classified as pathoge nic. The presence of a heterozygous pathogenic variant in PTPN11 is consistent w ith a diagnosis of Noonan syndrome but this information should be reconciled wit h the complete clinical history of this individual. |
Gene |
RCV000159052 | SCV000208994 | pathogenic | not provided | 2023-05-26 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 17339163, 19120036, 11992261, 28870985, 29907801, 29493581, 30050098, 32164556) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000587757 | SCV000698083 | pathogenic | Noonan syndrome 3 | 2016-02-29 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000687570 | SCV000815146 | pathogenic | RASopathy | 2024-11-20 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the PTPN11 protein (p.Phe285Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 15996221, 16358218, 17339163, 18470943, 21106241, 23321623, 23771920). ClinVar contains an entry for this variant (Variation ID: 44615). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. This variant disrupts the p.Phe285 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 15996221, 16358218, 18470943, 21106241, 23321623, 23771920). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
MGZ Medical Genetics Center | RCV002288537 | SCV002579183 | pathogenic | Noonan syndrome 1 | 2022-05-18 | criteria provided, single submitter | clinical testing |